The global burden of disease accounted for by epilepsy is equivalent to lung cancer in men and breast cancer in women, ranking it among the most serious neurological disorders. Our current and proposed research directly addresses benchmarks for research to prevent and cure epilepsy, developed by a joint committee of NINDS and the American Epilepsy Society. During the current funding period, we have characterized pathological high-frequency oscillations (pHFOs) as a potential reflection of the fundamental neuronal mechanisms underlying epilepsy, and as a putative biomarker of epileptogenesis and epileptogenicity. We now have acquired evidence from several chronic rat models of human mesial temporal lobe epilepsy (MTLE), and from patients with MTLE, suggesting that pHFOs are generated by discrete neuronal clusters embedded in tissue that does not generate pHFOs, and that an increase in size of these neuronal clusters with subsequent coalescence and synchrony could provide a mechanism for transition to ictus. Given the increasing importance of traumatic brain injury (TBI) and post-traumatic epilepsy (PTE) in returning veterans, we are now proposing to carry out similar studies in a fluid percussion model of TBI/PTE. Our preliminary data indicate that seizures in this model originate in hippocampus, have electrophysiological features resembling ictal onset patterns in rodent models of MTLE, and are associated with both interictal and ictal pHFOs. It is unknown, however, whether the hippocampus is the primary site of seizure generation in this model, or whether neocortical seizures also occur, and if so, whether hippocampal seizures reflect propagation from neocortex. Since the original submission of this proposal, we have recorded epileptiform discharges in neocortex anterior and posterior to the fluid percussion injury, as well as associated neocortical pHFOs. Consequently, we first propose to carry out long-term video-EEG monitoring with multiple microelectrodes to characterize the spatial and temporal patterns of epileptogenesis in this TBI model, and interictal juxtaneuronal recording and labeling to define the firing patterns of identified principal neurons and interneurons during pHFOs recorded from neocortical and hippocampal sites after spontaneous seizures occur. We will also carry out experiments similar to those we have performed in post-status rodent models of MTLE to determine whether mechanisms of transition to ictus are the same in the TBI/PTE rat model. We now have the capability to pursue more detailed and prolonged electrophysiological studies in patients with MTLE during depth electrode recording and will characterize the transition to the different seizure types exhibited by patients with this disorder. For many years, our research has utilized parallel experimental paradigms to investigate human MTLE and animal models of this disorder. We hope eventually to create the same parallel human/animal research paradigm for studying TBI. The ultimate goal of this research direction is to identify targets for intervention that will treat, prevent, or cure epilepsy, and to define reliable biomarkers of epilepsy.